The interferon (IFN) family of cytokines comprises both type I and type II subgroups. The type I subgroup is composed of IFNα, IFNω, IFNκ, IFNκ, and IFNτ and the type II subgroup is represented by IFNγ. Type I IFNs have multiple immunomodulatory effects including stimulation of polyclonal T cell responses, isotype switching, expression of class I major histocompatibility complex (MHC) molecules and induction of dendritic cell (DC) differentiation. Type I IFNs stimulate both macrophages and natural killer (NK) cells to elicit an anti-viral response, and are also active against tumors. Type I IFNs also act as pyrogenic factors by altering the activity of thermosensitive neurons in the hypothalamus, thus causing fever. A feature of the type I IFN system is rapid induction and amplification of signaling pathways, ensuring that a vigorous antiviral immune response is mounted.
However, while such pathways are highly effective for rapid virus eradication, this amplification can be maladapted in immune responses directed against host tissue, leading to autoimmune disease. Examples include systemic lupus erythematosus (SLE), rheumatoid arthritis and glomerulonephritis.
SLE is a chronic autoimmune disease in which immune defects lead to autoantibody production and subsequent inflammation and/or tissue damage in multiple organs, including skin, kidneys, blood, brain and joints. Disease course can be chronically active, relapsing and remitting or long-remitting. SLE is characterized by increased levels of many cytokines, including type I IFNs, such as IFNα.
Evidence for the role of IFNα in SLE has been demonstrated in several in vitro studies showing that serum from patients with SLE induced DC maturation from monocytes from normal mammals. Thus, serum from SLE patients could induce normally quiescent monocytes to become antigen presenting cells capable of inducing an immune response. Furthermore, suppression of IFNAR1 (the α chain of the receptor for type I IFN) expression in a mouse model of SLE (NZB mice) reduced hemolytic anemia, and reduced glomerulonephritis.
Clinically, patients with active SLE often have raised serum type I IFN levels, and these levels correlate positively with disease activity. Additional clinical evidence for a putative role of IFNα in SLE comes from the observation that patients without SLE treated with IFNα occasionally develop autoantibodies and clinical manifestations consistent with SLE.
Type I interferons are produced by many cell types including lymphocytes (NK cells, B-cells and T-cells), macrophages, fibroblasts, endothelial cells, ostcoblasts and certain dendritic cells. Plasmacytoid dendritic cells (pDCs) have been identified as being the most potent producers of type I IFNs in response to foreign antigens. pDCs are a subtype of circulating dendritic cells found in the blood as well as in peripheral lymphoid organs that are a source of type I interferons. Human pDCs typically express the surface markers IL-3 receptor α chain (IL-3Rα, CD123), BDCA-2 (CD303) and BDCA-4 (CD304), but do not express CD11c or CD14, which distinguishes them from conventional dendritic cells or monocytes, respectively. Upon stimulation and subsequent activation, pDCs produce large amounts of type I interferons (mainly IFN-α and IFN-β).
Given the apparent role for IFNα in type I IFN-dependent inflammatory diseases such as SLE, antibodies or soluble IFNAR proteins that neutralize the action of this cytokine are being pursued as potential therapeutic approaches.
An alternative approach suggested for the treatment of type I IFN-dependent inflammatory diseases such as SLE is to use compounds that bind to cell surface molecules expressed by type I interferon expressing cells.
A class of compounds that have been studied for the treatment of autoimmune diseases are immunotoxins comprising a single chain Fv (scFv) from an antibody conjugated to a toxin. These compounds have been suggested to be useful for killing IL-3Rα expressing cells. However, these molecules suffer from numerous disadvantages. For example, immunotoxins are known to cause liver and kidney damage. The small size of a toxin conjugated to a scFv may also mean that the immunotoxin is rapidly cleared by the kidneys, further exacerbating damage to this organ and meaning that the immunotoxin may not be retained in the body for sufficient time to confer a benefit. Furthermore, the toxin component is generally non-human meaning that they can induce an immune response in a patient. This immune response can neutralize the molecule. Accordingly, such immunotoxins may not be amenable to multiple treatments, which may be required to treat a chronic autoimmune disease.